Immune Checkpoint Blockade in Melanoma

Immune checkpoint blockade:
- Has fundamentally changed the management of cutaneous melanoma:
  - Including in the adjuvant setting and for local recurrence after prior therapies
- These agents, primarily anti–PD-1 antibodies (pembrolizumab, nivolumab) and anti–CTLA-4 (ipilimumab):
  - Work by releasing inhibitory signals on T cells:
    - Thereby enhancing antitumor immunity
  - This mechanism is particularly effective in melanoma:
    - A tumor type with high immunogenicity
Historically, adjuvant therapy for resected high-risk melanoma was limited to interferon-α:
- Which provided only modest benefit and significant toxicity
The introduction of immune checkpoint inhibitors:
- Especially anti–PD-1 agents:
  - Has led to substantial improvements in recurrence-free survival (RFS) and overall survival (OS):
    - With a more favorable toxicity profile compared to ipilimumab or interferon
The American Academy of Dermatology and major clinical trials:
- Have established anti–PD-1 therapy as the standard adjuvant approach for:
  - Resected stage III and select stage IV melanoma
Key randomized trials (KEYNOTE-054, CheckMate 238):
- Demonstrated that adjuvant pembrolizumab or nivolumab significantly improves RFS compared to placebo or ipilimumab:
  - With 3-year RFS rates of 63% to 70% in stage III disease and a reduction in the risk of recurrence or death by 40% to 50%
- These benefits are observed in both BRAF-mutant and wild-type melanoma:
  - The choice between immunotherapy and BRAF / MEK inhibitors in BRAF-mutant cases:
    - Is individualized based on toxicity profiles and patient preference
Despite these advances, local recurrence remains a clinical challenge:
- Approximately 25% to 30% of patients recur within 1 year of adjuvant anti–PD-1 therapy:
  - With a substantial proportion presenting with locoregional disease
Management of local recurrence after prior surgery or intralesional therapy is multidisciplinary:
- For resectable local recurrences:
  - Surgery remains the mainstay:
    - But systemic therapy is considered for unresectable, multifocal, or high-risk recurrences
- The effectiveness of immune checkpoint blockade in the setting of local recurrence depends on prior treatment history:
  - Patients who recur during or shortly after adjuvant anti–PD-1 therapy:
    - Have a low likelihood of response to further PD-1 monotherapy:
      - In these cases, escalation to combination immunotherapy (anti–PD-1 plus anti–CTLA-4) or switch to BRAF / MEK inhibitors (for BRAF-mutant melanoma) is recommended, as these approaches have demonstrated higher response rates
  - For patients who recur after a significant interval off adjuvant therapy:
    - Rechallenge with anti–PD-1 may be considered, as some may still respond
    - Retreatment and escalation strategies, including novel combinations, are under investigation, and clinical trial enrollment is encouraged for resistant or recurrent disease
- Toxicity remains a consideration, with immune-related adverse events:
  - Affecting skin, GI tract, endocrine organs, and other systems:
    - These are generally manageable but require prompt recognition and intervention:
  - Quality of life and patient selection are important, especially in the adjuvant and recurrent settings
In summary:
- Immune checkpoint blockade is the standard of care for adjuvant therapy in high-risk resected cutaneous melanoma and plays a central role in the management of local recurrence, particularly when escalation or combination strategies are employed after prior anti–PD-1 exposure
- Prospective data on optimal sequencing after adjuvant therapy and in local recurrence are limited, and management should be individualized within a multidisciplinary framework
References:
- Immune Checkpoint Inhibitors in Melanoma. Carlino MS, Larkin J, Long GV. Lancet (London, England). 2021;398(10304):1002-1014. doi:10.1016/S0140-6736(21)01206-X.
- Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. Patel SP, Othus M, Chen Y, et al. The New England Journal of Medicine. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437.
- Recent Advances in the Treatment of Melanoma. Curti BD, Faries MB. The New England Journal of Medicine. 2021;384(23):2229-2240. doi:10.1056/NEJMra2034861.
- Guidelines of Care for the Management of Primary Cutaneous Melanoma. Swetter SM, Tsao H, Bichakjian CK, et al. Journal of the American Academy of Dermatology. 2019;80(1):208-250. doi:10.1016/j.jaad.2018.08.055.
- Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont AMM, Blank CU, Mandala M, et al. The New England Journal of Medicine. 2018;378(19):1789-1801. doi:10.1056/NEJMoa1802357.
- Novel Adjuvant Options for Cutaneous Melanoma. Dimitriou F, Long GV, Menzies AM. Annals of Oncology : Official Journal of the European Society for Medical Oncology. 2021;32(7):854-865. doi:10.1016/j.annonc.2021.03.198.
- Monoclonal Antibodies as Adjuvant Therapies for Resected Melanoma. Eljilany I, Garcia JR, Jamal B, Tarhini AA. Expert Opinion on Biological Therapy. 2025;25(5):1-14. doi:10.1080/14712598.2025.2484305.
- Management of Early Melanoma Recurrence Despite Adjuvant Anti-Pd-1 Antibody Therapy. Owen CN, Shoushtari AN, Chauhan D, et al. Annals of Oncology : Official Journal of the European Society for Medical Oncology. 2020;31(8):1075-1082. doi:10.1016/j.annonc.2020.04.471.
- Nature and Management of Melanoma Recurrences Following Adjuvant Anti-Pd-1 Based Therapy. Woodford R, McKeown J, Hoeijmakers LL, et al. European Journal of Cancer (Oxford, England : 1990). 2024;212:115055. doi:10.1016/j.ejca.2024.115055.
- Treatment of Recurrent Melanoma Following Adjuvant Therapy. Malissen N, Grob JJ. American Journal of Clinical Dermatology. 2023;24(3):333-341. doi:10.1007/s40257-023-00762-y.
- The Concepts of Rechallenge and Retreatment With Immune Checkpoint Blockade in Melanoma Patients. Zaremba A, Eggermont AMM, Robert C, et al. European Journal of Cancer (Oxford, England : 1990). 2021;155:268-280. doi:10.1016/j.ejca.2021.07.002.